We are using the vitamin B12 receptor to target the delivery of cytotoxic anticancer drugs to rapidly dividing cells in leukemia and to solid tumors. Specific drug-B12 bioconjugates (general term to include either drug-cobalamin or drug-corrinoid bioconjugates) are synthesized by attaching various cytotoxic warheads to cobalamin or a structurally- related corrinoid through the cobalt atom. The active cytotoxic drug is released spontaneously inside of immature leukemia cells, but no toxicity is observed when receptor-mediated endocytosis is blocked by presaturation of the B12 receptors with vitamin B12. In solid tumors and all other tissues, the pro-drug is nontoxic until it is activated by photolysis with tissue-penetrating red light, or with sonolysis with focused ultrasound. We have prepared chlorambucil-cobalamin and our results in vitro with human leukemia cells and human colon tumor cells show this to be a very effective method to increase the therapeutic index of drugs. For the immediate budget period, we will prepare bioconjugates of five additional cytotoxic anticancer drugs: carboplatin, busulfan, doxorubicin, etoposide, and topotecan. Bioconjugates of authentic B12 (cobalamin), as well as a close analogue of B12 that has a more favorable absorption spectrum in the red region will be used. The stability of these bioconjugates, as well as their decomposition under photolytic and sonolytic conditions will be studied, and their toxicity against various NCI human cancer cell lines in vitro will be evaluated. Bioconjugates that show favorable activity in vitro will be provided to a collaborator at the Mayo Clinic for independent animal testing.